CN1681494A - 4-(3,5-Dicyanophenoxy)pyrazole derivatives useful as reverse transcriptase modulators in the treatment of I.A. HIV - Google Patents
4-(3,5-Dicyanophenoxy)pyrazole derivatives useful as reverse transcriptase modulators in the treatment of I.A. HIV Download PDFInfo
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Abstract
The present invention relates to pyrazole derivatives of formula and pharmaceutically acceptable salts, solvates or derivatives thereof, to their use in medicine, to compositions containing them, to processes for their preparation, and to intermediates used in such processes. The compounds of the invention bind to reverse transcriptase and are modulators, especially inhibitors, thereof. Reverse transcriptase is involved in the infectious life cycle of Human Immunodeficiency Virus (HIV). Compounds that interfere with the function of this enzyme are useful in the treatment of conditions caused by HIV and genetically related retroviruses, such as acquired immunodeficiency syndrome (AIDS).
Description
The present invention relates to pyrazole derivatives, their application in medicine comprise their compositions, their preparation method and in this intermediates useful in such preparation.
Reverse transcriptase relates to the infection life cycle of HIV (human immunodeficiency virus) (HIV).Confirmed to disturb the chemical compound of this enzyme function to can be used for treating the disease that causes by HIV and the upward relevant retrovirus of heredity, as acquired immune deficiency syndrome (AIDS) (AIDS).Because virus can make a variation, and known regulator is developed immunity to drugs, people always constantly need the regulator, particularly inhibitor of new better hiv reverse transcriptase.
, disclose in 2000,43,1034 at J.Med.Chem. as a class N-phenyl pyrazoles material of reverse transcriptase inhibitors.In US patent 3,303,200, describe class N-(ethoxy) pyrazole derivatives and had antiviral activity.Recapitulative having comprised but concrete following formula (I) chemical compound that do not disclose in still undocumented International Application PCT/IB02/01234 of the application's the applying date.
Chemical compound of the present invention can combine with reverse transcriptase, and is the regulator of this enzyme, particularly inhibitor.
According to the present invention, provide formula (I) chemical compound
Or its officinal salt, solvate or derivant.
The officinal salt of formula (I) chemical compound comprises its acid-addition salts and alkali salt.
Suitable acid-addition salts is generated by the acid that can form nontoxic salts, and the example has hydrochlorate, hydrobromate, hydriodate, chloride, bromide, iodide, sulfate, disulfate, nitrate, phosphate, hydrophosphate, acetate, fumarate, embonate, aspartate, benzene sulfonate, carbonate, bicarbonate, camsilate, D and L-lactate, D and L-tartrate, esilate, mesylate, malonate, Orotate, gluceptate, Methylsulfate, stearate, glucuronate salt, the 2-naphthalene sulfonate, toluene fulfonate, hybenzate, nicotinate, isethionate, malate, maleate, citrate, gluconate, succinate, glucarate, benzoate, esilate and embonate.
Suitable alkali salt is generated by the alkali that can form nontoxic salts, and the example has sodium salt, potassium salt, aluminum salt, calcium salt, magnesium salt, zinc salt, choline salt, diethanolamine salt (diolamine), ethanolamine salt, arginine salt, glycinate, trometamol salt, benzyl spread Sal (benzathine), lysinate, meglumine salt and diethyl amine salt.
These suitable salt are referring to people's such as Berge J.Pharm.Sci., and 66,1-19,1977 and people's such as Bighley Encyclopedia of Pharmaceutical Technology, MarcelDekker Inc, New York, 1996,13 volumes, 453-497 page or leaf.
The pharmaceutically useful solvate of formula (I) chemical compound comprises hydrate.
Formula (I) chemical compound can be modified on any functional group of chemical compound and obtain its pharmaceutically useful derivant.The example of these derivants has description in following document: Drugs of Today, the 19th volume (9), 1983, pp 499-538; Topics in Chemistry, the 31st chapter, pp306-316; And " Design of Prodrugs ", H.Bundgaard, Elsevier, 1985, the 1 chapters (the disclosed content of these documents is incorporated herein by reference).These derivants comprise: ester, carbonic ester, half ester, phosphate ester, nitrate (nitro ester), sulfuric ester, sulfoxide, amide, sulfonamides, carbamate, azo-compound, phosphamide, glucosides, ethers, acetal and ketal.
The present invention includes all isomeric forms of formula (I) chemical compound and officinal salt, solvate or derivant, it comprises all geometric isomers, tautomer and optical isomer, and their mixture (for example racemic mixture).
The separation of diastereomer can be finished by the technology of routine, for example, the stereoisomer mixture of chemical compound is carried out fractional crystallization, chromatographic isolation or high performance liquid chromatography (HPLC).The single enantiomer of chemical compound also can be from corresponding optically pure intermediate preparation, perhaps can split corresponding racemic modification, or obtain by the diastereomeric salt fractional crystallization that corresponding racemic modification and suitable optically active acid or alkali reaction are formed by the HPLC that for example uses suitable chiral support.
Formula (I) chemical compound can be with multiple different form crystallization with its officinal salt, solvate or derivant, and this feature is called as polymorphism, and all these polycrystalline forms (polymorph) all comprise within the scope of the invention.The variation of common Yin Wendu of polymorphism and/or pressure and taking place, and can in crystallization process, produce various variations.Polymorph can be distinguished by various physical features, and is typically the fusing point of X-ray diffraction pattern, solubility behavior and chemical compound, and these may be used to distinguish polymorph.
Formula (I) chemical compound, its officinal salt, solvate and derivant, isomer and polymorph all are called chemical compound of the present invention hereinafter.
The preferred chemical compound of the present invention is formula (I) chemical compound and officinal salt and solvate.
Most preferred of the present invention is formula (I) chemical compound.
Chemical compound of the present invention has superior performance, comprises good metabolic stability, and thereby has a good pharmacokinetic properties.In addition, chemical compound of the present invention is more more superior than those materials of the prior art at many other useful aspect of performances, as usefulness, active duration, drug effect scope, side reaction, dissolubility, chemical stability or the like.
Chemical compound of the present invention can be by the method preparation of the chemical compound of preparation similar structures known in the art.Chemical compound of the present invention can prepare by method described below, or presses the ad hoc approach preparation that embodiment describes, or by the method preparation that is similar to two kinds of methods.The present invention comprises that also one or more prepare the method for The compounds of this invention, also comprises the new intermediate that all are used therein.
Formula (I) chemical compound can prepare by following scheme 1 described approach:
Scheme 1
In scheme 1, formula (I) chemical compound can through type (II) chemical compound and the 2-hydroxyethyl hydrazine of formula V or its salt or hydrate condensation obtain, this reaction is chosen wantonly in the presence of acid or alkali and is carried out, preferably tertiary amine base such as triethylamine of alkali wherein, and acid is acetic acid preferably.In a representational method, with the solution of formula (II) chemical compound in appropriate solvent such as acetic acid with the hydrazine of formula V or its salt or hydrate and, if you are using, suitable acid or alkali treatment, reaction temperature is the reflux temperature that room temperature arrives solvent.In a preferable methods, reaction is at room temperature carried out.
In this reaction, also can use formula (II) compound functions equivalent.It comprises formula (VI) or chemical compound (VII), wherein L
1And L
2Be respectively suitable leaving group, preferred-N (C
1-C
6Alkyl)
2, most preferably-N (CH
3)
2
Therefore, formula (I) chemical compound can obtain by compound or its salt or the hydrate condensation with formula (VI) or chemical compound (VII) and formula V, and this reaction is randomly carried out in the presence of acid or alkali, and alkali is preferably tertiary amine base such as triethylamine, and acid is preferably acetic acid.In a representational method, with formula (VI) or (VII) solution of chemical compound in appropriate solvent such as ethanol with formula V compound or its salt or hydrate and, if you are using, suitable acid or alkali treatment, reaction temperature is the reflux temperature that room temperature arrives solvent.In a preferable methods, reaction is carried out under reflux.
L
1For formula (VI) chemical compound of dimethylamino can through type (VIII) chemical compound and the Methanamide acetal that suitably replaces prepared in reaction at elevated temperatures.Preferred reaction temperature is 100 ℃.L
1For can through type (IX) chemical compound reacting under identical condition, the chemical compound of the formula (VII) of dimethylamino obtains.
The chemical compound of formula (VIII) can be commercially available, or can through type (X) chemical compound and the reaction of formula (XI) chemical compound make.In a representational method, the solution of formula (XI) chemical compound in appropriate solvent such as acetone is handled with the chemical compound of suitable alkali such as cesium carbonate and formula (X).In a preferred method, reactant mixture is heated to for example backflow.Randomly, can be to wherein adding nucleophilic catalyst such as sodium iodide or tetrabutylammonium iodide.
The chemical compound of formula (IX) can be commercially available, also can prepare according to the same procedure from formula (X) compound formula (VIII) chemical compound from formula (XII) chemical compound and formula (XI) chemical compound.
Chemical compound that formula (II) chemical compound can through type (III) and the reaction of the chemical compound of formula (XI) obtain.
In a representational method, the solution of formula (III) chemical compound in appropriate solvent such as acetone with formula (XI) chemical compound and suitable alkali such as potassium carbonate or cesium carbonate processing and heating, preferably is heated to backflow.Randomly, can be to wherein adding nucleophilic catalyst such as sodium iodide or tetrabutylammonium iodide.
The chemical compound of formula (III) can be commercially available, or chemical compound that can through type (IV) and chlorination reagent reaction obtain.In a representational method, the solution of refrigerative formula (IV) chemical compound in appropriate solvent such as acetonitrile is at first handled with Tetrabutylammonium bromide and trim,ethylchlorosilane, use exsiccant dmso treatment then.In another representational method, the chemical compound of formula (IV) is handled with chlorosulfuric acid, in this reaction, randomly there are appropriate solvent such as dichloromethane.
Formula (I) chemical compound can also be by obtaining the pyrazole compound of formula (XIII) and the alkylating reagent of formula (XIV) or the derivatives reaction of its protection.
In a representational method; with the pyrazole compound of formula (XIII) at appropriate solvent such as ethanol or N; solution in the dinethylformamide ethoxy bromide of the alkylating reagent of formula (XIV) as protection; with alkali such as Sodium ethylate or sodium hydride processing, heating-up temperature is 0 ℃ of reflux temperature to solvent.Preferred combination is with N, and dinethylformamide is a solvent, and sodium hydride is an alkali, under 0 ℃, is that alkylating reagent reacts with 2-(2-bromine oxethyl) tetrahydrochysene-2H-pyrans.
It will be understood by those skilled in the art that in the alkylated reaction of the pyrazole compound of formula (XIII), need or wish the oh group of formula (XIV) chemical compound is protected that in this case, formula (I) chemical compound finally will be by to having-OP accordingly
1The chemical compound of group carries out deprotection reaction and can prepare, wherein P
1It is suitable blocking group.The example of due care group is conspicuous for those of ordinary skill; For example referring to " Protecting groups in Organic Synthesis (second edition) "; Theodora W.Green and Peter G.M.Wuts, 1991, John Wiley andSons is (especially referring to the 10-118 page or leaf; protection about oh group), the document is incorporated herein by reference.Have-OP
1The chemical compound of group can be done necessary change in detail by aforementioned similar method preparation.
Formula (IV) and the commercially available acquisition of chemical compound (V), be known or can easily make in the document by method well known to those skilled in the art.
Chemical compound of the present invention can be individually dosed, but usually all be with suitable pharmaceutical excipient, the diluent or carrier form administration with mixture.Described excipient, diluent or carrier as required route of administration and the pharmacy practice of standard select.
For example, chemical compound of the present invention can be with the form of tablet, capsule, many granules, gel, diaphragm, ovule, elixir, solution or suspending agent by in oral, the cheek or the administration of Sublingual, wherein can contain correctives or coloring agent, be used for the rapid release administration, postpone release administration, sustained-release administration, continue medication, pulsatile administration or controlled release drug administration.Chemical compound of the present invention can also be with quick dispersion or rapidly-soluble dosage form administration, or with the form administration of high energy dispersions, or with the form administration of coated granule.The suitable preparation of The compounds of this invention can adopt the coating or the form of coating not as required.
Described solid composite medicament, tablet for example, can contain excipient, as microcrystalline Cellulose, lactose, sodium citrate, calcium carbonate, calcium hydrogen phosphate, glycine and starch (preferred corn starch, potato starch or tapioca), disintegrating agent, as Explotab, cross-linking sodium carboxymethyl cellulose and specific composition silicate, and particle binders, as polyvinylpyrrolidone, hydroxypropyl emthylcellulose (HPMC), hydroxypropyl cellulose (HPC), sucrose, gelatin and arabic gum.In addition, can also comprise lubricant such as magnesium stearate, stearic acid, glyceryl behenate and Pulvis Talci.
General embodiment
Tabules typically comprises the active substance of 0.01-500mg, and the weight range that tablet is filled is at 50-1000mg.The embodiment of a 10mg Tabules is as described below:
Composition %w/w
Chemical compound 10.000 of the present invention
*
Lactose 64.125
Starch 21.375
Cross-linking sodium carboxymethyl cellulose 3.000
Magnesium stearate 1.500
*According to the activity of medicine, the corresponding adjustment of content.
The preparation of tablet is finished according to a conventional method, for example direct compression process, dry method or wet granulation process.Label can carry out suitable coating.
The solid composite of similar type can be used to fill gelatin or HPMC capsule.Preferred excipient comprises lactose, starch, cellulose, lactose (milk sugar) or high-molecular weight Polyethylene Glycol.For aqueous suspensoid and/or elixir, can be with chemical compound of the present invention and various sweeting agent or correctives, pigment or dyestuff, emulsifying agent and/or suspending agent, diluent such as water, ethanol, propylene glycol and glycerol, and their mixture mixes.
Chemical compound of the present invention can also pass through the parenteral route administration, for example administration in administration in administration in intravenously administrable, intra-arterial administration, intraperitoneal administration, intrathecal drug delivery, the ventricle, the urethra, the breastbone, intracranial administration, intramuscular or subcutaneous administration perhaps pass through transfusion or the administration of Needleless injection technology.For the parenteral administration form, preferably use and contain some other composition, for example make the form of the aseptic aqueous solution of the salt of solution and the isoosmotic capacity of blood or glucose.If necessary, aqueous solution should suitably cushion (preferably to pH3-9).The suitable non-gastrointestinal preparation of preparation can be finished at an easy rate by the pharmaceutical technology of standard well known to those skilled in the art under aseptic condition.
For the oral and parenteral administration to the patient, the dosage level of chemical compound of the present invention is generally 0.01-30mg/kg, preferably 0.01-5mg/kg (giving with single agent or divided dose form).
Therefore, the tablet of The compounds of this invention or capsule can contain the reactive compound of 1-500mg, are used for single agent administration, or when needed, two doses of single administrations or multi-agent.Under any circumstance, the doctor can determine to be suitable for most the actual dose of individual patients, and what this dosage can be according to age, body weight and the reaction of particular patient is different and different.Above-mentioned dosage is the example of ordinary circumstance.Certainly, for some was individual, higher or lower dosage range was useful, therefore was also included within the scope of the present invention.It will be understood by those skilled in the art that when some disease of treatment, need or wish the form administration of chemical compound of the present invention with single agent.
All right intranasal administration of chemical compound of the present invention or inhalation, and can pass through inhaler with dry powdered form easily, or with spray form by pressure vessel, air pump, aerosol apparatus or nebulizer release, wherein, can use or not use suitable propellant such as dichlorodifluoromethane, Arcton 11, dichlorotetra-fluoroethane, hydrogenation fluoric ether as 1,1,1, the 2-tetrafluoroethane (HFA 134A[trade mark]) or 1,1,1,2,3,3,3-seven fluoro-propanes (HFA 227EA[trade mark]), carbon dioxide or other suitable gas.For the pressure aerosol, but dosage unit is determined by the valve that measured quantity is provided.Pressure vessel, air pump, aerosol apparatus or nebulizer can contain the solution or the suspension of reactive compound, and the mixture of for example using ethanol and propellant can also contain lubricant such as sorbitan trioleate in addition as solvent.Suck or insufflator in the capsule that uses and cartridge case (making) can pack into chemical compound of the present invention and the suitable powder substrate such as the mixture of powders of lactose or starch by for example gelatin.
Perhaps, chemical compound of the present invention can be with the form administration of suppository or vaginal suppository, or can be with the form topical of gel, hydrogel, washing liquid, solution, cream, ointment or face powder.All right percutaneous of chemical compound of the present invention or transdermal administration for example, carry out administration by using skin patch.They can also be by the administration of lung or rectum.
They can also pass through through the eye administration.For the application of ophthalmology, particle suspension agent that this chemical compound can be formed in is isoosmotic, pH regulator is crossed, in the Sterile Saline, or, can randomly add antiseptic, as benzalkonium chloride preferably at isoosmotic, that pH regulator is crossed, in the Sterile Saline solution.Perhaps, they can also make ointment, as vaseline.
Topical application for skin, chemical compound of the present invention can be made and comprise the suitable ointment that suspends or be dissolved in the reactive compound in the following mixture, and described mixture contains following one or more compositions: mineral oil, liquid Paraffin, white vaseline, propylene glycol, polyoxyethylene polyoxypropylene chemical compound, emulsifing wax and water.Perhaps, they can also make suitable lotion or cream, suspend or be dissolved in for example to contain in one or more following mixture of ingredients: mineral oil, anhydrosorbitol monostearate, Polyethylene Glycol, liquid Paraffin, polysorbate60, cetyl esters wax, 16/octadecanol, 2-octyldodecanol, benzyl alcohol and water.
Chemical compound of the present invention can also be used for making up with cyclodextrin.Known cyclodextrin can form the complex of drug molecule enclose and non-enclose.The formation of drug-cyclodextrin complex can improve the stability of dissolubility, rate of dissolution, bioavailability and/or drug molecule.The drug-cyclodextrin complex can be used for most drug dosage form and route of administration usually.Except direct and medicine form the complex, cyclodextrin can also be used as adjuvant additive, for example carrier, diluent or solubilizing agent.α-, β-and gamma-cyclodextrin be the most frequently used cyclodextrin, its suitable example is described among WO-A-91/11172, WO-A-94/02518 and the WO-A-98/55148.
Should be appreciated that treatment described here comprises healing property, the property alleviated and preventative treatment.
Oral administration is preferred.
The specific embodiment among the present invention comprises chemical compound of the present invention and one or more other therapeutic agent co-administereds, and comprises the compositions of chemical compound of the present invention and one or more other therapeutic agents.Such therapeutic alliance is used in particular for preventing and/or treating HIV and relevant retroviral infection, and these viruses can have chemical sproof strain by the paired any single therapy of tachytelic evolution.Perhaps, may need other therapeutic agent to treat and treat disease caused or that followed with The compounds of this invention.For example, in treatment HIV or relevant retroviral infection, may need additional procedures opportunistic infection, tumor and other is because the disease that patient's immunocompromise state takes place.
Preferred therapeutic alliance of the present invention comprises that using chemical compound of the present invention simultaneously or sequentially treats with one or more following medicines:
(a) reverse transcriptase inhibitors is as Abacavir, adefovirdipivoxil, Didanosine, lamivudine, stavudine, zalcitabine and zidovudine;
(b) non-nucleoside reverse transcriptase inhibitor is as capavirine, delavirdine, efavirenz and nevirapine;
(c) hiv protease inhibitor such as indinavir, nelfinavir, ritonavir and Saquinavir;
(d) CCR5 antagonist such as TAK-779 or UK-427,857;
(e) CXCR4 antagonist such as AMD-3100;
(f) integrase inhibitor, as L-870,810 or S-1360;
(g) viral fusion inhibitor is as T-20;
(h) novel drugs in the research, as three associations only, KNI-272, amprenavir, GW-33908, FTC, PMPA, MKC-442, MSC-204, MSH-372, DMP450, PNU-140690, ABT-378, KNI-764, DPC-083, TMC-120 or TMC-125;
(i) antifungal is as fluconazol, Itraconazole or voriconazole; Or
(j) antibacterial agent is as Azithromycin.
The compounds of this invention can be measured by following analytical method as the activity of reverse transcriptase inhibitors.
HIV-1 reverse transcriptase inhibitory action
Recombinant HIV-1 reverse transcriptase (the RT that passes through the escherichia coli expression acquisition of application of purified, EC, 2.7.7.49), set up 96-hole Analysis of Plate and measure system to measure a large amount of samples, use Poly (rA)-widow (dT) reverse transcriptase [3H]-SPA enzymatic determination system (Amersham NK9020) and [3H]-Flashplate enzymatic determination system (NEN-SMP 103) simultaneously, use according to the explanation of manufacturer.Compound dissolution also is diluted to 5% DMSO final concentration with suitable buffer in 100% DMSO.The inhibition activity is used with respect to the inhibition percent of the matched group of DMSO and is represented.Chemical compound suppresses reverse transcriptase and reaches the IC that 50% concentration is expressed as chemical compound
50Value.
Measure the IC of embodiment 1 chemical compound by above step
50Value is 295 nanomoles.
Following assay is used in the metabolism of The compounds of this invention.
A. at human hepatomicrosome and Supermix
TM
In metabolism
The compounds of this invention is at hepatomicrosome and Supermix
TMIn the metabolism unstability can measure as follows.
Microsome fraction separates from human liver and measures P450 content.Supermix
TMObtain from Gentest.With human microsome (0.5 μ M Cytochrome P450) and Supermix
TM(0.05 μ M Cytochrome P450) joins and contains 50mM phosphate buffer (pH value 7.4), 5mMMgCl
2, 1mM NADP and the NADPH generation system formed by 1-Hydroxy-1,2,3-propanetricarboxylic acid. and Isocitrate dehydrogenase culture medium in.Concentration of substrate is 1 μ M, and cultivates 1 hour down at 37 ℃.Different time points in incubation is extracted sample and is used the hplc-ms-ms method and analyze.
The t of the chemical compound of the embodiment 1 of Ce Dinging according to the method described above
1/2＞120 minutes (human microsome and Supermix
TMAll like this).
B. the metabolism in human hepatocytes
The metabolism unstability of The compounds of this invention in human hepatocytes can be measured by the following method.
Cryopreserved human hepatocytes derives from In vitro Technologies company.Hepatocyte thawed and with the concentration of 100 ten thousand cell/ml at 50% Krebs-Heinsleit buffer: suspend in 50% the Williams E culture fluid that comprises 10% hyclone.Concentration of substrate is 3 μ M, and cultivates 3 hours down at 37 ℃.Different time points in incubation is extracted sample and is used the hplc-ms-ms method and analyze.
The non-binding hepatocyte removing value of the chemical compound of the embodiment 1 of Ce Dinging is＜9ml/ minute/kg according to the method described above.
Therefore, the invention provides:
(i) formula (I) compound or pharmaceutically acceptable salt thereof, solvate or derivant;
The (ii) preparation method of formula (I) compound or pharmaceutically acceptable salt thereof, solvate or derivant;
(iii) comprise formula (I) compound or pharmaceutically acceptable salt thereof, solvate or derivant, reach the pharmaceutical composition of pharmaceutically useful excipient, diluent or carrier;
(iv) be used as formula (I) compound or pharmaceutically acceptable salt thereof, solvate or the compositions of medicine;
(v) be used as formula (I) compound or pharmaceutically acceptable salt thereof, solvate or the compositions of reverse transcriptase inhibitors or regulator;
(vi) be used for the treatment of the upward relevant retroviral infection of HIV or heredity, or formula (I) compound or pharmaceutically acceptable salt thereof, solvate or the compositions of the acquired immune deficiency syndrome (AIDS) that causes thus (AIDS);
(vii) formula (I) compound or pharmaceutically acceptable salt thereof, solvate or compositions have reverse transcriptase in preparation and suppress or regulate application in the active medicine;
(viii) formula (I) compound or pharmaceutically acceptable salt thereof, solvate or compositions are used for the treatment of retroviral infection relevant in HIV or the heredity in preparation, or the application in the medicine of the acquired immune deficiency syndrome (AIDS) that causes thus (AIDS);
(ix) a kind ofly treat HIV or relevant retroviral infection is gone up in heredity, or the method for the acquired immune deficiency syndrome (AIDS) that causes thus (AIDS), comprise formula (I) compound or pharmaceutically acceptable salt thereof, solvate or the compositions that give effective dose; With
(xi) some new intermediate disclosed herein.
Following examples are used for the preparation of formula (I) chemical compound.Here synthesizing in the preparation example of embodiment back of the specific intermediate of Ying Yonging partly made description.
All
1H nuclear magnetic resonance, NMR (NMR) collection of illustrative plates conforms to the structure of expectation.Characteristic chemical displacement value (δ) adopts conventional abbreviation to specify main peak to provide to low field-biased 1,000,000/(ppm) of tetramethylsilane, for example: s, unimodal; D, bimodal; T, triplet; Q, quartet; M, multiplet; Br, broad peak.Using following abbreviation is described: HRMS, high resolution mass spec; Hplc, high performance liquid chromatography; NOe, nuclear Overhauser effect; M.p., fusing point; CDCl
3, deuterochloroform; D
6-DMSO, deuterated dimethyl sulfoxide; CD
3OD, deuterated methanol.When using thin layer chromatography (TLC), refer to and use silica gel 60 F
254The silica gel tlc of plate, R
fValue is meant the development distance of chemical compound in the TLC plate and the ratio of solvent front development distance.
Embodiment 1
5-{[3-cyclopropyl-1-(2-ethoxy)-5-methyl isophthalic acid H-pyrazoles-4-yl] the oxygen base } isophthalonitrile
Under blanket of nitrogen and room temperature, (1.15ml, (4.1g is in acetic acid 15.4mmol) (40ml) solution 16.9mmol) to join the diketone of preparation example 7 with 2-hydroxyethyl hydrazine.Stir after 18 hours,, the oil of remnants by fast silica gel chromatogram method purification, is used ethyl acetate: pentane (50: 50 → 100: 0, volume ratio) eluting, two kinds of regional isomer samples that obtain being further purified the mixture concentrating under reduced pressure.
Low polar fraction obtains with the isolated in form of yellow solid (1.2g), obtains colourless acicular title compound (600mg) with toluene (5ml) its sample of recrystallization (815mg).The sample (580mg) of this material is further carried out purification by preparation property HPLC, use Luna C8 (II) 150 * 21.2mm10 μ m post, water with 95: 5: acetonitrile (0.1% trifluoroacetic acid aqueous solution) and acetonitrile (0-1 minute were, 100: 0, in 1 minute, become 70: 30 then, carried out 18 minutes, and in 1 minute, became 100: 0 then) eluting, obtain the sample of title compound.This material is removed all residual acid by being dissolved in dichloromethane (50ml) with saturated sodium bicarbonate aqueous solution (50ml) washing.The organic facies dried over mgso is filtered and concentrating under reduced pressure, obtains cystose product (270mg), with toluene (5ml) recrystallization, obtains colourless acicular title compound sample (265mg).M.p.127-128℃。
1H?NMR(400MHz，CDCl
3)：δ＝0.84(m，4H)，1.58(m，1H)，2.13(s，3H)，4.03(m，2H)，4.13(m，2H)，7.42(s，2H)，7.59(s，1H)。
LRMS (atmospheric chemical ionization): m/z[MH
+] 309.
Microanalysis: measured value C, 66.14; H, 5.24; N, 18.15.C
17H
16N
4O
2Require C, 66.22; H, 5.23; N, 18.17%.
Confirm that by nOE NMR regional isomer is arranged, and clearly identify by the x-ray crystal analysis method.
The fraction of high polarity is further by fast silica gel chromatogram method purification, use ethyl acetate: toluene (50: 50, volume ratio) eluting, obtain 5-{[5-cyclopropyl-1-(2-ethoxy)-3-methyl isophthalic acid H-pyrazoles-4-yl] the oxygen base } isophthalonitrile (structure is as follows), be white solid (90mg), M.p.129-130 ℃.
1H?NMR(400MHz，CDCl
3)：δ＝0.68(m，2H)，0.87(m，2H)，1.58(m，1H)，2.03(s，3H)，4.07(m，2H)，4.31(m，2H)，7.39(s，2H)，7.59(s，1H)。
LRMS (atmospheric chemical ionization): m/z[MH
+] 309.
Embodiment 2
5-{[3-cyclopropyl-1-(2-ethoxy)-5-methyl isophthalic acid H-pyrazoles-4-yl] the oxygen base } isophthalonitrile
Stir down, to the pyrazoles of preparation example 9 (250mg, add in methanol 0.64mmol) (6ml) solution right-toluenesulfonic acid (12mg, 0.06mmol).After 18 hours, reactant mixture is concentrated, (20ml w/v) and between the dichloromethane (20ml) distributes residue at 10% wet chemical.(2 * 20ml) washings merge organic facies to water layer, use dried over mgso, filter and concentrate, and obtain the title compound (195mg) of faint yellow oily, and it need not be further purified direct use with dichloromethane.
1H NMR (400mHz, CDCl
3), with above-mentioned consistent.
LRMS (thermal spray methods): m/z[MH
+] 309.
Preparation example 1
1,3-two bromo-5-methoxybenzenes
Under 0 ℃ and the blanket of nitrogen, (the 4.5M methanol solution of 8.80ml 39.6mmol) under agitation drops to 3, and (5.00g, the 19.0mmol) N of (Aldrich) is in dinethylformamide (95ml) solution for 5-dibromo fluorobenzene with Feldalat NM.Reaction is warming up to room temperature, stirs concentrating under reduced pressure 1 hour.Residue is dissolved in (500ml) in the ether, and water (3 * 300ml) and saline (300ml) washing, use dried over mgso, filtration, concentrating under reduced pressure obtains white solid product (5.13g).
1H-NMR(300MHz，CDCl
3)：δ＝3.79(s，3H)，7.00(s，2H)，7.26(s，1H)。
LRMS (thermal spray methods): m/z[MH
+] 266.
Microanalysis: measured value: C, 31.56; H, 2.29.C
7H
6OBr
2Need C, 31.62; H, 2.27%.
Preparation example 2
3,5-dicyano methoxybenzene
Under room temperature and blanket of nitrogen, with three (dibenzalacetones), two palladiums (O) (6.53g, 7.15mmol) the disposable bromide (38.0g that joins preparation example 1,143mmol), 1,1 '-two (diphenylphosphino) ferrocene (9.3g, 16.8mmol) and zinc cyanide (20.0g, N 172mmol) is in dinethylformamide (300ml) solution.Reaction is heated to 100 ℃ of reactions 14 hours, is cooled to room temperature then.Add entry (1500ml), mixture ethyl acetate extraction (3 * 500ml).Merge organic facies, filter, dried over mgso is used in filtrate water (500ml) washing, filters and concentrating under reduced pressure, and the gained solid adds toluene (1000ml) and grinds, and obtains title compound (18.0g), is brown solid.
1H-NMR(300MHz，CDCl
3)：δ＝3.83(3H，s)，7.31(2H，s)，7.48(1H，s)。
Preparation example 3
3,5-dicyano hydroxy benzenes
Under 0 ℃ and the blanket of nitrogen, (9.60g, 60.7mmol) under agitation be added to aluminum chloride (32.4g is in dichloromethane 243mmol) (250ml) suspension in batches with the nitrile of preparation example 2.Suspension is heated to 45 ℃, and stirs 6 days.Reaction is cooled to room temperature, carefully is poured onto on ice (450ml).Drip concentrated hydrochloric acid (450ml), the gained suspension at room temperature stirred 10 minutes.Filter and collect the gained solid, wash with water, after the phosphorus pentoxide drying, obtain title compound (7.83g), be brown solid,
1H-NMR and microanalysis show, wherein contain about 11% raw material.
1H-NMR(400MHz，CDCl
3)：δ＝7.36(m，2H)，7.56(m，1H)。
Preparation example 4
The 3-ketobutyric acid
(37.9g 0.947mol) is dissolved in the water (770ml), and (100g is 0.861mol) in (Aldrich) under agitation to drop to 3-oxo-methyl butyrate with 20 fens clock times in room temperature with sodium hydroxide.Stirred 18 hours, with ammonium sulfate (700g) cessation reaction, and slow water (250ml) solution with concentrated hydrochloric acid (21.5ml) carries out acidify under ice bath.Reactant mixture with diethyl ether (6 * 200ml) extractions merge organic facies, use dried over mgso, filter also concentrating under reduced pressure, obtain title compound (58.2g), are faint yellow oily thing, its be ketone and enol tautomers mixture (as
1Shown in the H NMR).
1H NMR (400MHz, CDCl
3): δ=2.00 (s, 3H-enol), 2.30 (s, 3H-ketone), 3.51 (s, 2H-ketone), 5.02 (s, 1H-enols).
Preparation example 5
1-cyclopropyl-1, the 3-diacetyl
(3.04g 125mmol) is heated under the situation of logical nitrogen and refluxed 1 hour, is cooled to room temperature, at ice-cooled beta-keto acid (25.5g, methanol 250mmol) (25ml) solution that drips preparation example 4 down will to be suspended in magnesium chips in the methanol (145ml).Reaction was at room temperature stirred 1 hour, and solvent is removed in decompression, obtained the magnesium salt of acid.Simultaneously, with cyclopropane-formic acid (9.91ml 125mmol) is dissolved in the dimethyl formamide (200ml), and under the situation of 0 ℃ and logical nitrogen, add carbonyl dimidazoles in batches (22.4g, 138mmol).Stirred 1.5 hours, at 0 ℃ of dimethyl formamide (100ml) solution that adds above-mentioned magnesium salt down.Reaction was at room temperature stirred 92 hours, and mixture is poured in the 2M aqueous hydrochloric acid solution (85ml), water (170m1) dilution subsequently.(6 * 200ml) extractions merge organic facies to mixture, and (3 * 200ml) washings are used dried over mgso, concentrating under reduced pressure with saline with diethyl ether.Residual orange is used pentane by fast silica gel chromatogram method purification: diethyl ether (100: 0 → 90: 10 is 80: 20 then, volume ratio) eluting, obtain title compound (7.39g), and it is a yellow oil.
1H?NMR(400MHz，CDCl
3)：δ＝0.89(m，2H)，1.08(m，2H)，1.59(m，1H)，2.00(s，3H)，5.61(s，1H)，15.62(s，1H)。
LRMS (electron spray method): m/z[MNa
+] 149.
Preparation example 6
2-chloro-1-cyclopropyl-1, the 3-diacetyl
Under the condition of room temperature and logical nitrogen, (18.9ml, (932mg 2.89mmol) in the solution in dry acetonitrile (50ml), is cooled to 0 ℃ with mixture 174mmol) to be added to tetrabutyl ammonium bromide with trim,ethylchlorosilane.Add preparation example 5 diketone (7.3g, acetonitrile 57.9mmol) (36ml) solution, drip subsequently exsiccant dimethyl sulfoxide (12.3ml, 174mmol).Be reflected at 0 ℃ and stirred 1.5 hours down, mixture water (500ml) dilution with diethyl ether (2 * 200ml and 100ml) extraction, merges organic facies, uses dried over mgso, filters and concentrating under reduced pressure.Remaining grease is used pentane by fast silica gel chromatogram method purification: diethyl ether (100: 0 → 95: 5 is 90: 10 then, volume ratio) eluting, obtain title compound (5.76g), and be colorless oil.
1H?NMR(400MHz，CDCl
3)：δ＝1.04(m，2H)，1.18(m，2H)，2.27(s，3H)，2.42(m，1H)，15.78(s，1H)。
LRMS (electron spray method): m/z[M-H
+] 159.
Preparation example 7
5-[1-(cyclopropyl carbonyl)-2-oxopropoxy] isophthalonitrile
With cesium carbonate (6.01g, 18.5mmol) and derive from the phenol (2.66g of preparation example 3,18.5mmol) under agitation, (2.46g, in acetone 15.4mmol) (75ml) solution, reaction was stirred 3 hours to join the diketone of preparation example 6 under the condition of logical nitrogen and 60 ℃.Acetone is removed in the decompression of cooling back, and the gained residue distributes between 1N aqueous hydrochloric acid solution (100ml) and dichloromethane (100ml).Water phase separated is with dichloromethane (50ml) extraction.Merge organic facies, use dried over mgso, concentrating under reduced pressure obtains title compound, and it is Off-white solid (4.2g).
1H?NMR(400MHz，CDCl
3)：δ＝0.92(m，2H)，1.19(m，2H)，1.78(m，1H)，1.99(s，3H)，7.47(m，2H)，7.62(m，1H)。
LRMS (electron spray method): m/z[M-H
+] 267.
Preparation example 8
5-[(3-cyclopropyl-5-methyl isophthalic acid H-pyrazoles-4-yl) oxygen base] isophthalonitrile
(298 μ l, 6.16mmol) (1.50g is in acetic acid 5.60mmol) (22ml) solution leading to the diketone that joins preparation example 7 under nitrogen and the room temperature with hydrazine hydrate.After stirring 18 hours under 50 ℃, mixture is cooled to room temperature and concentrating under reduced pressure.Residue distributes between 10% wet chemical (50ml) and dichloromethane (50ml).Isolate water layer, use twice (2 * 50ml) of washed with dichloromethane.Merge organic facies, use dried over mgso, filter and concentrating under reduced pressure, obtain faint yellow oily thing.Crude product is used pentane by fast silica gel chromatogram method purification: ethyl acetate (75: 25 → 67: 33, volume ratio) eluting, obtain title compound (1.20g), and be faint yellow oily thing.
1H?NMR(400MHz，CDCl
3)：δ＝0.75(m，2H)，0.85(m，2H)，1.60(m，1H)，2.10(s，3H)，7.40(s，2H)，7.60(s，1H)。
LRMS (thermal spray methods): m/z[MH
+] 260.
Preparation example 9
5-({ 3-cyclopropyl-5-methyl isophthalic acid-[2-(tetrahydrochysene-2H-pyrans-2-base oxygen base) ethyl]-1H-pyrazoles-4-yl } oxygen
Base) isophthalonitrile
(420mg adds sodium hydride (the 60%w/w suspension of 70mg in mineral oil) in dimethyl formamide 1.59mmol) (4ml) solution to the pyrazoles of the preparation example 8 that stirs under 0 ℃.Remove cooling bath after finishing, mixture at room temperature stirred 30 minutes.Add 2-(2-bromo ethyoxyl) tetrahydrochysene-2H-pyrans (264 μ l, 1.75mmol) solution in dimethyl formamide (2ml).After 2 hours, in reactant mixture, add entry (20ml) cessation reaction, with dichloromethane (3 * 20ml) extractions.Merge organic facies, (dried over mgso is used in 2 * 20ml) washings, filters, and obtains yellow oil after concentrating with saline.Crude mixture is used dichloromethane by fast silica gel chromatogram method purification: methanol (100: 0 → 98: 2, volume ratio) eluting obtains the mixture (594mg) of two kinds of regional isomers.These two kinds of regional isomers separate by the fast silica gel chromatogram method, use toluene: ethyl acetate (100: 0 → 80: 20,75: 25,67: 33 and 50: 50 volume ratios) eluting, obtain title compound (257mg) (low polar fraction) and its regional isomer (90mg) (high polar fraction).
Low polar fraction
1H?NMR(400MHz，CDCl
3)：δ＝0.78(m，4H)，1.55(m，5H)，1.67(m，2H)，2.12(s，3H)，3.45(m，1H)，3.65(m，1H)，3.75(m，1H)，4.04(m，1H)，4.18(m，2H)，4.53(m，1H)，7.40(s，2H)，7.59(s，1H)。
LRMS (thermal spray methods): m/z[MH
+] 393.
High polar fraction
5-({ 5-cyclopropyl-3-methyl isophthalic acid-[2-(tetrahydrochysene-2H-pyrans-2-base oxygen base) ethyl]-1H-pyrazoles-4-yl } oxygen
Base) isophthalonitrile
1H?NMR(300MHz，CDCl
3)：δ＝0.68(m，2H)，0.85(m，2H)，1.53(m，3H)，1.72(m，4H)，2.10(s，3H)，3.51(m，1H)，3.72(m，1H)，3.83(m，1H)，4.17(m，1H)，4.35(m，2H)，4.58(m，1H)，7.38(s，2H)，7.59(s，1H)。
LRMS (thermal spray methods): m/z[MH
+] 393.
Claims (11)
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| DE102008062863A1 (en) | 2008-12-17 | 2010-06-24 | Aicuris Gmbh & Co. Kg | Substituted (thiophenyl-carbonyl) imidazolidinones and their use |
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